title: Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer.
abstract: BACKGROUND
  The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact.
  
  
  RESULTS
  We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples.
  
  
  CONCLUSIONS
  Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.
authors.affiliation: Department of Urology and Pediatric Urology, Comprehensive Cancer Center (CCC) Mainfranken, University Hospital, Würzburg, Germany. Schubert_M@klinik.uni-wuerzburg.de
authors.forename: Maria
authors.initials: M
authors.lastname: Schubert
authors.forename: Martin
authors.initials: M
authors.lastname: Spahn
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: Claus Jürgen
authors.initials: CJ
authors.lastname: Scholz
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.forename: Philipp
authors.initials: P
authors.lastname: Stroebel
authors.forename: Hubertus
authors.initials: H
authors.lastname: Riedmiller
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018572:Disease-Free Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D034622:RNA Interference; D012306:Risk; D059467:Transcriptome; D017211:Treatment Failure
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D025741:HMGA1a Protein